Patient-Reported Status and Heart Failure Outcomes in Asia by Sex, Ethnicity, and Socioeconomic Status

Background In heart failure (HF), symptoms and health-related quality of life (HRQoL) are known to vary among different HF subgroups, but evidence on the association between changing HRQoL and outcomes has not been evaluated. Objectives The authors sought to investigate the relationship between changing symptoms, signs, and HRQoL and outcomes by sex, ethnicity, and socioeconomic status (SES). Methods Using the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) Registry, we investigated associations between the 6-month change in a “global” symptoms and signs score (GSSS), Kansas City Cardiomyopathy Questionnaire overall score (KCCQ-OS), and visual analogue scale (VAS) and 1-year mortality or HF hospitalization. Results In 6,549 patients (mean age: 62 ± 13 years], 29% female, 27% HF with preserved ejection fraction), women and those in low SES groups had higher symptom burden but lower signs and similar KCCQ-OS to their respective counterparts. Malay patients had the highest GSSS (3.9) and lowest KCCQ-OS (58.5), and Thai/Filipino/others (2.6) and Chinese patients (2.7) had the lowest GSSS scores and the highest KCCQ-OS (73.1 and 74.6, respectively). Compared to no change, worsening of GSSS (>1-point increase), KCCQ-OS (≥10-point decrease) and VAS (>1-point decrease) were associated with higher risk of HF admission/death (adjusted HR: 2.95 [95% CI: 2.14-4.06], 1.93 [95% CI: 1.26-2.94], and 2.30 [95% CI: 1.51-3.52], respectively). Conversely, the same degrees of improvement in GSSS, KCCQ-OS, and VAS were associated with reduced rates (HR: 0.35 [95% CI: 0.25-0.49], 0.25 [95% CI: 0.16-0.40], and 0.64 [95% CI: 0.40-1.00], respectively). Results were consistent across all sex, ethnicity, and SES groups (interaction P > 0.05). Conclusions Serial measures of patient-reported symptoms and HRQoL are significant and consistent predictors of outcomes among different groups with HF and provide the potential for a patient-centered and pragmatic approach to risk stratification.

H eart failure (HF) prevalence is projected to increase by 40% by 2035, 1 with the fastest rates of increase in developing countries. 2 The prevalence of HF in some parts of Asia is 2 to 3 times that found in Europe and United States, with patients presenting as much as 20 years younger. 3 HF is associated with multiple comorbidities, high hospitalization and mortality rates, 4,5 and profoundly worse healthrelated quality of life (HRQoL) when compared to the healthy population and to many other chronic diseases. [6][7][8] Current guidelines recommend regular and systematic monitoring of clinical status to optimize treatments, facilitate early recognition of clinical change, and improve outcomes. 9 Several techniques routinely used in clinical practice to monitor HF clinical status include assessing the patients' signs and symptoms, functional status, and exercise capacity as well as measurement of biomarkers. Prior evidence shows that changes in self-reported functional status and HRQoL closely align with symptom changes 10 and more closely parallel physician assessments of change in clinical status than the NYHA classification, exercise capacity, weight change, or Btype natriuretic peptide level, 11 and there have been recent calls to integrate serial recordings of HRQoL into interventional trials 12 and routine clinical care. 13 A key challenge to using patient-reported measures in prognosis is that patients' experiences of symptoms and health may differ according to social or cultural characteristics. Evidence on patientreported health status in different groups with HF is limited, but recent reports have shown that HRQoL differs by socioeconomic status (SES), 14 country, 15 and ethnicity. [16][17][18] Although evidence over 2 decades has shown a clear association between baseline symptoms, signs, 19,20 HRQoL, [21][22][23][24][25][26][27][28] and outcomes in HF, there is emerging evidence that its relationship with outcomes may also be moderated by country of origin 15 and ethnicity. 29 However, evidence on changing clinical status in different HF subgroups has not been evaluated.
Using a multinational, multiethnic HF registry, the objective of this study was to examine the association between different measures of clinical status change with 1-year hospitalization or death and to determine the influence of sex, ethnicity, and socioeconomic status on these associations using serial measures of:

Symptoms and
signs. HF entails multiple signs and symptoms of congestion (swelling of the ankles or abdomen, dyspnea) and fatigue. 9 We extracted information regarding the presence or absence of 13 symptoms and signs recorded at entry to the registry and at Non-English-speaking participants used certified versions of the KCCQ translated into their native languages. Patients were stratified into 4 baseline health categories from "best" to "worst" using prior literature: "best" for 76 to 100, "good" for 51 to 75, "bad" for 26 to 50, and "worst" for 0 to 25. Change in KCCQ-OS was estimated using the difference between the baseline and the 6-month measure. Clinically meaningful change in KCCQ-OS is considered to be a change of 5 points or more 11 ; therefore, change over 6 months was categorized as "considerable worsening of $10-point change," "mild worsening of 5 to 9 points," "no significant change" as a <5-point change, "mild improvement of 5 to 9 points," and "consider- Visual analogue scale. HRQoL can be assessed using multi-item validated patient-reported health questionnaires or using a single-item "global" question about health. Single-item scales correlate highly with outcomes and are easy to apply. We used a singleitem visual analogue scale (VAS) to assess the current health perception at baseline and at 6 months.
The VAS was administered by having the patients mark the point on a 10-cm (100-mm) line that best corresponds to their current perceived health status, with 0 reflecting "worst possible health" and 10 Values are mean AE SD, n (%), or median (IQR). a KCCQ-OS available in n ¼ 5,427 participants.
reflecting "perfect health." We categorized the baseline VAS score by the median value (6.0) to create 2 categories (VAS low: <6; VAS high: $6). For change in VAS over 6 months, we created 3 change categories: "no change" as a 1-point change or less, "worsening" as a >1-point decrease in score, and "improvement" as a >1-point increase in score.
ETHNICITY. Participants were categorized according to their self-reported ethnicity status on entry to the register as Chinese, Indian, Malay, Japanese/Korean, or Thai/Filipino/others. SOCIOECONOMIC STATUS. Low SES was defined by no formal or less than primary education and monthly household income of USD#$1,000. High was defined as secondary education and higher or monthly household income of USD$$1,000.
COVARIATES. We considered a range of clinically important variables, including the sociodemographic factors: age, sex, geographic region (Northeast, South, and Southeast Asia), education level (none or primary, secondary, preuniversity, degree or higher), regional income level (low-, middle-, and highincome region) and monthly household income (USD<$1,000; USD$1,000-USD$2,999; USD$$3,000); HF factors: inpatient or outpatient enrolment, NYHA functional class, heart rate, and blood pressure;     (Figure 1). Women had a higher prevalence of all 3 symptoms than men but a lower    Figure 3 for unadjusted survival curves).  The number at risk refers to the number of patients included in each analysis (those patients with follow-up data and known outcomes recorded). Ethnicity is a categorical variable including Chinese, Indian, Malay, Korean/ Japanese, and Thai/Filipino/other. a Adjusted for New Yor Heart Association functional class; age; sex; ethnicity; enrollment type; regional income level; ejection fraction; systolic blood pressure; heart rate; chronic obstructive pulmonary disease; atrial fibrillation; diabetes; coronary artery disease; chronic kidney disease; peripheral arterial vascular disease; and use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta blockers, or mineralocorticoid receptor antagonists (and baseline GSSS, KCCQ, or VAS for the respective change measures). Tables 1 and 2 Table 3).  We found that overall patient-reported HRQoL and its change was a superior indicator of prognosis compared to signs and symptoms. Whereas there was a significantly higher symptom burden in women than men and in low compared to high SES groups, the overall GSSS and KCCQ-OS scores were similar across groups at baseline. This contrasts to prior reports of worse health in women and in lower SES groups compared to their respective counterparts.   were representative of single country registers. By using prevalent cases of HF, we could not adjust for the duration of HF. Nevertheless, we did include severity measures in our analysis among a range of other essential adjustment factors. Some groups were small, and these findings need further investigation in larger cohorts to elucidate any differences among groups fully and interventional studies to determine the utility of HRQoL measures with or without signs and symptoms. The GSSS was developed to provide a summary of the overall "severity" of signs and symptoms as assessed by the physician, but further testing is required evaluate the individual contribution of the symptoms and signs components as well as different cutpoints. Further work is also needed to explore the influence of HF subtype.

DISCUSSION
Although we adjusted for ejection fraction, we could not further stratify by subtype given the smaller numbers by group characteristics.

CONCLUSIONS
Serial measures of self-reported symptoms and health are predictive of outcomes in HF among different groups of patients and provide the potential for a patient-centered, cost-effective, and straightforward approach to risk stratification. Health service providers should consider the routine recording of Values are adjusted HR (95% CI). HRs adjusted for New York Heart Association functional class; age; sex; enrollment type; regional income level; ejection fraction; systolic blood pressure; heart rate; chronic obstructive pulmonary disease; atrial fibrillation; diabetes; coronary artery disease; chronic kidney disease; PAVD; and use of angiotensinconverting enzyme inhibitors/angiotensin receptor blockers, beta blockers, or mineralocorticoid receptor antagonists.
patient-reported information to guide shared decision making and care.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
The ASIAN-HF study is supported by grants from Boston Scientific